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How do real tumors become resistant to cisplatin?

机译：真正的肿瘤如何对顺铂耐药？

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Lab research on cultured tumor cells selected for resistance to platinum compounds has turned up a diverse array of resistance mechanisms. In contrast, we recently found that mouse mammary tumors containing irrepairable null alleles of the Brca1 gene do not become resistant to cisplatin ever, although they invariably become resistant to a variety of other anti-cancer drugs. Each new treatment with cisplatin shrinks the tumor to a very small remnant, but relapse always occurs. The BRCA1 missing in these mouse tumors is essential for the homology-directed DNA repair (HR) that allows error-free repair of the duplex breaks caused by the excision of platin-DNA adducts. The mouse tumor results therefore raise the question whether the cisplatin resistance mechanisms identified in vitro can actually overcome an irreversible defect in DNA repair in real tumors. This question is underlined by recent analyses of tumor samples of patients with ovarian cancer that have uncovered a new platin resistance mechanism: these tumors were initially sensitive to platin through a defect in the BRCA2 gene, also required for HR, like BRCA1. Resistance in these patients,-after an initial response of the tumor,-was due to secondary mutations in the defective BRCA2 gene, restoring BRCA2 function.(1,2) These clinical observations show the overriding importance of a functional HR system for tumor cells to survive platin-induced DNA lesions. Taken together with the mouse mammary tumor data, these observations raise the possibility that proliferating cells have no readily available mechanism to escape from cisplatin DNA damage once their HR is irreversibly inactivated.
机译：对被选择对铂化合物具有抗性的培养肿瘤细胞的实验室研究发现了多种抗性机制。相反，我们最近发现，含有不可修复的Brca1基因无效等位基因的小鼠乳腺肿瘤对顺铂没有抗药性，尽管它们始终对多种其他抗癌药有抗药性。每次使用顺铂的新疗法都会使肿瘤缩小到很小的残留量，但总是会复发。在这些小鼠肿瘤中缺失的BRCA1对于同源性指导的DNA修复（HR）是必不可少的，该修复允许无损修复由铂-DNA加合物的切除引起的双链断裂。因此，小鼠肿瘤的结果提出了一个问题，即在体外确定的顺铂耐药机制是否能真正克服真实肿瘤中DNA修复中不可逆的缺陷。最近对卵巢癌患者的肿瘤样本进行了分析，突显了这个问题，该样本已经发现了新的铂耐药机制：这些肿瘤最初是通过BRCA2基因缺陷对铂敏感的，而BRCA2基因也是HR所必需的，例如BRCA1。这些患者的抗药性，是在肿瘤最初反应后，归因于缺陷的BRCA2基因的继发突变，恢复了BRCA2的功能。（1,2）这些临床观察表明，功能性HR系统对于肿瘤细胞至关重要在铂诱导的DNA损伤中存活。结合小鼠乳腺肿瘤数据，这些观察结果提出了一旦其HR不可逆地失活，增殖细胞就无法从顺铂DNA损伤中逃脱的机制。

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